Kevin Kozak, M.D. & Ph.D. Assistant Professor Department of Human Oncology kozak@humonc.wisc.edu

Research Interests:

Globally, I am interested in identifying molecular, cellular and organ-level barriers to effective anti-neoplastic therapy and developing methods to overcome, or exploit, these barriers. Specifically, I am currently examining vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (e.g. axitinib, motesanib, sunitinib). A newly recognized class-effect of these agents is a compensatory upregulation of an array of pro-angiogenic molecules (e.g. VEGF) and downregulation of a complementary set of anti-angiogenic molecules (e.g. sVEGFR-2). This observation raises several possibilities with immediate clinical relevance. With tyrosine kinase inhibitor discontinuation, for toxicity, disease progression or cyclic therapy, the resultant proangiogenic mileau may drive brisk rebound angiogenesis. Furthermore, several of the modulated proteins may provide a mechanism for anti-angiogenic escape - neovascularization in the setting of persistent VEGFR inhibition. Using cellular, murine and human systems, our laboratory is asking the following questions:

1. Does angiogenic rebound with VEGFR inhibitor discontinuation promote primary and/or metastatic tumor growth? If so, which specific molecular pathways mediate this process?
2. Should VEGFR inhibition be delivered continuously, even in the face of apparent resistance, to avoid angiogenic rebound? Can drug tapering or a complementary targeted agent be used to blunt the impact of the rebound?
3. Can the rebound be exploited therapeutically? Could a cytotoxin, such as ionizing radiation, be added at the peak of the rebound to maximize therapeutic benefit?

Prospective Molecular and Cellular Pharmacology graduate students will be exposed to a wide-range of experimental techniques in pursuit of answers to these questions. Our laboratory has experience with synthetic chemistry, nuclear magnetic resonance spectroscopy, mass spectrometry, protein mutagenesis, expression and purification, proteomics, enzymology, molecular biology, immunohistochemistry, xenograft mouse models (both heterotopic and orthotopic) and human clinical trials. Importantly, close collaboration with colleagues in the Department of Human Oncology, including Paul Harari, Ajit Verma and Deric Wheeler, will provide prospective students access to scientists with broad-ranging expertise and access to clinicians to ensure the efforts in the laboratory remain closely tied to pressing, patient-oriented problems.

Recent Publications: Articles on PubMed

• Dunn, E. F., Kozak, K. R. and Moody, J. S. (2009) External beam radiotherapy for colon cancer: patterns of care. Int. J. Radiat. Oncol. Biol. Phys. Accepted.

• Kozak, K. R. and Moody, J. S. (2009) Giant cell glioblastoma: a glioblastoma subtype with distinct epidemiology and superior prognosis. Neuro-Oncol. Epub ahead of print.

• Moody, J. S., Sawrie, S. M., Kozak, K. R., Plastaras, J. P., Howard, G. and Bonner, J. A. (2009) Stage-specific survival differences associated with postoperative radiotherapy for gastrointestinal cancers. J. Gastrointest. Cancer Epub ahead of print.

• Plastaras, J. P. and Kozak, K. R. (2009) A one, two punch for liver cancer. Cancer Biol Ther. Epub ahead of print.

• Kozak, K. R., Mahadevan, A. and Moody, J. S. (2008) Adult gliosarcoma: epidemiology, natural history and factors associated with outcome. Neuro-Oncol. Epub ahead of print.

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